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Abstract

The early diagnosis of cancer can help direct the best treatment strategy and improve patients' survival. The unique and tunable properties of nanoparticles facilitate the development of diagnostic imaging tools for earlier diagnosis and disease staging, and they can provide fundamental information on the pathological process. Nanoparticle probes have demonstrated to have numerous advantages over single molecule-based contrast agents, such as tumor-targeted delivery via the enhanced permeability and retention (EPR) effect, prolonged systemic circulation times to enhance imaging contrast efficiency, and facile surface modification for specific applications. The first part of this dissertation focuses on the development of radiation- damaged nanodiamonds (DNDs), a type of carbon-based nanoparticles, for the detection of solid tumors using a photoacoustic (PA) imaging technique. In chapter 2 of this dissertation, DNDs are proposed as ideal optical contrast agents for PA imaging in biological tissues due to their low toxicity and high optical absorbance. A new DND with very high NIR absorption was synthesized by He+ ion beam irradiation. These DNDs produced a 71-fold higher PA signal on a molar basis than similarly dimensioned gold nanorods, which were considered the "gold" standard agent for PA contrast agents. In order to develop DNDs as a molecularly-targeted contrast agent for high resolution and phenotype-specific detection of breast cancer with PA imaging, in chapter 3, an anti- Human epidermal growth factor receptor-2 (HER2) peptide (KCCYSL) was conjugated to the surface of PEGylated DNDs. PA images demonstrated that DNDs accumulate in orthotopic HER2 positive tumors and completely delineated the entire tumor within 10 hours. Chapters 4 and 5 of this dissertation describe the development of a hyaluronic acid (HA) polymeric nanoparticle to deliver drugs for the locoregional treatment of head and neck squamous cell carcinoma (HNSCC). In chapter 4, a HA-pyropheophorbide a (PPa) conjugate was synthesized. The anti-cancer efficacy was improved compared to the intravenously administered PPa molecules, and it was demonstrated that it could be useful for in vivo locoregional photodynamic therapy of HNSCC. In chapter 5, a pH- tunable delivery platform of platinum-based anti-cancer drug was designed and synthesized to improve the therapeutic index. The systemic toxicity of cisplatin was significantly reduced due to the pH-controlled release of the active forms of Pt species. In chapter 6, a lanthanum label was non-covalently conjugated to HA polymer to track the in vivo bio-distribution of HA in HNSCC tumors and organs that are responsible for the elimination of nanoparticles. In the last chapter, an enzymatic N-deacetylation method was applied in the modification on HA. New synthetic routs were explored to prepare HA derivatives for anti-cancer drug delivery to meet specific needs with retained HA characteristics.